A lack of folate in the diet of male mice reprograms their sperm in ways that damage their offspring. Could the same be true in men?

DOCTORS recommend that women who are pregnant, or plan to be, eat plenty of green, leafy vegetables. These are a source of vitamin B9—or folate, as it is also known—a substance that helps embryos develop by encouraging the formation of the neural tube, the precursor to the brain and the spinal cord. Folate has never been recommend to putative fathers, though, for the obvious reason that, sperm apart, a father contributes nothing to the physical substance of an embryo.

If the results of research on mice, by Sarah Kimmins and her colleagues at McGill University, in Montreal, are found to apply to people too, that may need to change. For, as they report in Nature Communications, they have discovered something odd: that folate deficiency in fathers can, in rodents at least, be as debilitating for embryos as deficiency in mothers. An absence of folate when sperm are forming causes alterations in them that affect the mice which grow from the eggs those sperm fertilise. In particular, Dr Kimmins saw serious deformities of head, spine and limbs.

This damage seems to be caused by epigenetic modification, the subject of a rapidly emerging field of research. Such modification involves a process called methylation, which alters the behaviour of genes in a way that can be passed from one generation to another. Folate’s job is to regulate methylation. How epigenetic modification might cause the defects Dr Kimmins saw, she does not yet know. But when she and her team looked at changes in the methylation patterns of genes in the sperm of folate-deficient rats they found things there that might cause other phenomena, which are not apparent at birth. These include cancer, diabetes, and even autism and schizophrenia.

Marked for death

Dr Kimmins and her team raised male mice that had had a low exposure to folate for the whole of their lives, from conception onwards. In other words, not only they, but also their mothers were fed this diet. Once born, these males were otherwise treated normally, and when mature were introduced to females and allowed to mate. The researchers then followed what happened.

Their first observation was that the folate-deficient males were less fertile than otherwise-comparable control animals. Only 52% of the females they were mated with became pregnant, compared with 85% of those mated with controls. And even among those females that did become pregnant, twice as many pregnancies ended with the fetuses being reabsorbed by the mothers if the father was folate deficient.

Then, when the pups were born, those fathered by the deficient males were much more likely to be deformed. Some 27% of such litters included pups with visible abnormalities, compared with 3% of litters fathered by controls. These abnormalities included hydrocephalus (“water on the brain”), deformed spines and limbs with missing toes.

When they compared the DNA of sperm from folate-deficient males with that from the sperm of males which had had a normal diet, the researchers found 57 places whose methylation patterns differed. These included the sites of 18 genes known in humans to be involved in cancer, six that are involved in various forms of diabetes and seven that have been implicated in autism or schizophrenia.

Whether these abnormal methylation patterns are actually carried into the body cells of animals sired by such sperm, the researchers have not yet found out. Nor is it clear what the effects would be if they were, or whether such effects would be found in people as well as mice.

The researchers note, however, that the causes of more than 40% of birth defects in children in the rich world remain unknown. They also note that the number of people with diabetes in America alone has risen from 6m in 1985 to more than 20m now. Many cancer rates are rising too, and research is throwing up examples of tumours caused by epigenetic modifications of unknown origin. All this suggests it is worth investigating the idea that epigenetically modified sperm may be a previously unrecognised source of disease.

The other point worth noting is that, although some epigenetic modification takes place when sperm cells form (shortly before they are ejaculated), much of it happens early in embryonic development, when the progenitors of those cells come into being. At this point it is the diet of the mother carrying the embryo which matters. How much good it will really do men to change what they eat to improve their sperm is thus moot. It may be that the damage is actually caused before they have any say in the matter.